Introduction

Over the last years, hot melt extrusion (HME) has attracted significant interest in the pharmaceutical industry. HME is performed at elevated process temperatures that cause the material to soften or even melt. Thereby, the formation of molecular solid dispersions is possible, given that the formulation and the HME process are carefully designed.

Molecular solid dispersions are advantageous, since they yield improved bioavailabilities [1, 2], which is a common problem in the delivery of poorly soluble drugs (e.g. [3, 4]). The reason for improved bioavailabilities is twofold: First, in a molecular dispersion the drug size is maximally reduced. Second, molecular dispersions frequently contain the drug in its amorphous state, which shows increased apparent solubility compared to its crystalline counterpart. Moreover, advanced formulations (i.e., co-crystals and in situ salts) or structured products (i.e., by co-extrusion) can be obtained.

HME does not readily deliver a final formulation product that can be administered to the patient. Instead, HME provides molten material that needs to be further processed via a downstream process. Thereby, a variety of different dosage forms, including intermediate products that need further processing (e.g., granules), are manufactured. This clearly shows that, after HME, a variety of additional processing steps are required, which may affect the final dosage form performance and stability.

Similar to HME, injection molding (IM) is a melt processing technique. It offers the opportunity to directly process molten material into a final product of any desired shape, while maintaining the advantages of a solid dispersion. IM is a semi-continuous process and comprises five processing steps (Figure 1). During IM thermoplastic materials are typically melted using a single-screw extruder (Figure 1, Step 1). The molten material is accumulated in the antechamber in front of the screw and plasticization is completed when a predefined volume is reached (Figure 1, Step 2). Subsequently, the molten material is injected into a closed, shape-specific mold cavity (Figure 1, Step 3), where it cools down and solidifies. During the packing and cooling step, the injection pressure is maintained to supply the mold with fresh material. Thereby, volume shrinkage during cooling is compensated. Finally, the product (e.g. tablet) is ejected from the mold (Figure 1, Step 5).

In certain cases IM can be applied to directly process the primary powders (i.e., drug and excipients) into a final dosage form. However, most frequently, IM is applied to process homogeneous material manufactured via HME, since conventional IM uses single-screw plasticizing units with limited mixing capabilities. Thereby, application of the primary powders as feeding material would yield an inhomogeneous product with poor in-vivo performance.

The present study addresses production of tablets via IM that contain a poorly soluble model drug as an amorphous solid dispersion. Therefore, we applied a simple two-component system comprising fenofibrate as the model drug and polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®, BASF) as the matrix former. Due to its poor water solubility, fenofibrate dissolution is expected to limit fenofibrate absorption. Consequently, proper formulation strategies need to be applied to ensure efficient and safe patient treatment.

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Methods

Pellets containing 10% fenofibrate and 90% graft copolymer were prepared via HME. Subsequently, the pellets were processed into tablets in a single step using an Engel e-mac 50/50 IM machine (Figure 2A) equipped with an 18 mm single-screw plasticizing unit. The mold was constructed with a cold runner system and six cavities (Figure 2B). Individual tablets were obtained by manually removing the sprue. The shape of the mold served to produce cylindrical tablets with a diameter of 13 mm and a height of 5 mm.

The tablets were characterized via differential scanning calorimetry (DSC) with respect to the solid state of both fenofibrate and the graft copolymer. Moreover, the effect of the solid state on the in-vitro dissolution performance was evaluated.

Results and Discussion

Tablets prepared via IM were yellowish with a smooth surface (Figure 3). They were glassy in their appearance and their weight was 620 mg, corresponding to a single dose of 62 mg fenofibrate for 10% drug loading. The cycle time during IM was approximately 1 min, which allows production of 360 tablets per hour. The yield (i.e., ratio of tablet weight to total weight) was rather low, i.e., around 40% with the used setup. This can be improved by applying a hot runner system and/or a higher number of cavities in the mold, which will be the focus of future work.

The solid state of fenofibrate of the pellets prepared via HME and of the tablets prepared via IM was investigated using DSC. For comparison reasons, the primary powders and the physical blend resembling the formulation were investigated as well. The results are summarized in Figure 4: The thermogram of the physical blend shows an endothermic peak around 80°C correlating to the melting of fenofibrate. As the glass transitions of Soluplus occurs at the same temperature of 80°C, it was not clearly detectable in the thermogram of the physical blend. Once the powder blend was subjected to a thermal process that was HME and IM, the thermograms did not include the melting peak of fenofibrate, indicating the absence (or only very low amounts) of crystalline drug. This suggests formation of a solid dispersion containing both, fenofibrate and the graft copolymer in their amorphous states during HME and IM. Consequently, the dissolution rates of fenofibrate pellets prepared via HME and tablets manufactured via IM were markedly increased compared to the powder blend (Figure 5). Obviously, fenofibrate dissolution was not improved by simply blending the drug with the polymer, but by thermal treatment of the blend. Fenofibrate release from the pellets was rapid and was completed within 30 minutes. The tablets release profiles showed a zero-order release mechanism over two hours in hydrochloric acid, where, finally, 60% of the drug was found in the dissolution medium. Clearly, the dissolution profiles of pellets and tablets were different, although the DSC measurements indicated that both, pellets and tablets contained fenofibrate in its amorphous state. The differences are not attributed to the solid-state characteristics, but to decreased surface-to-volume ratios of tablets compared to pellets. Hence, according to the Noyes-Whitney equation, the dissolution rate is slowed for identical drug loadings and diffusion coefficients.

Conclusion and Outlook

Overall, the IM process applied was suitable for tablet production, which yield improved dissolution characteristics of fenofibrate due to the formation of a solid dispersion.

The focus of our work is to gain a fundamental understanding of processing, release and stability behavior of IM tablets, based on detailed material and process characterization, such as viscosity and melt behavior, miscibility, thermal behavior, just to mention some examples. Deep process understanding reduces development effort during transfer from screening methods to pilot scale production. Furthermore, it allows tailoring product properties to a significant extent. Thus, it is a necessary prerequisite for a successful implementation of injection molding as manufacturing technology in the pharmaceutical industry.

PSSRC Facilities

The “Pharmaceutical Engineering and Particle Technology” area at the Institute of Process and Particle Engineering has developed from a group of researchers around Prof. Johannes Khinast in Fall 2005. Initially focused on catalysis and direct numerical simulations of bubbly flows, Prof. Khinast’s group has formed three sub-groups dedicated to research in the fields of applied chemistry and continuous processing, manufacturing processes for the pharmaceutical industry, and simulation science. In a highly interdisciplinary environment, our area is eager to gain a more fundamental understanding of

transport process in (bio)reactors,

production of heterogeneous catalysts and (nano)particles,

(chromatographic) separation processes,

pharmaceutical polymer processing,

multiphase and granular flows, as well as

transport processes in complex fluids.

A main focus, with respect to teaching, is student training in the area of pharmaceutical engineering, transport phenomena and particle technology. Our research complements that of our sister organization “Research Center Pharmaceutical Engineering GmbH”, and is tightly connected to leading national and international research institutions. This makes our area an attractive partner for the industry, and brings us into a position for applying and winning Austria- and Europe-wide research grants.Please find further information at: http://ippt.tugraz.at

Introduction

The production and manufacturing of solid pharmaceutical products is in need of new technologies to ensure a safe and efficient medical therapy. Hot melt extrusion (HME) is a new and innovative technology in the field of pharmaceutics, which aids to overcome numerous limitations of traditional manufacturing techniques. The benefit of HME is three-fold: First, the bioavailability of poorly soluble drugs is significantly increased due to the conversion of the drug from the crystalline into its amorphous state [1]. Recent work showed that HME is even capable of converting a liquid nanosuspension into a solid formulation in a one-step process [2], thereby avoiding aggregation of nanocrystals. Second, drug release profiles can be specifically tailored (in most cases retarded release of water soluble drugs) via the application of a proper matrix carrier in combination with plasticisers [3]. Third, drug abuse can be prevented due to superior mechanical properties of the final product [4].

However, there are still challenges, which need to be overcome during the development of a hot melt extruded product. During formulation design a suitable combination of carrier and additives must be identified to achieve the desired final dosage form properties. Here, it is especially important to guarantee dosage form stability over shelf life. During process development the melt extrusion process and downstream processing need to be optimised. The downstream is chosen on basis of the target dosage form; commonly, extrudates are milled prior to compression into tablets. However, several alternatives are available, including die face pelletising, shaping calander, strand cutting, etc. We focus on the development/establishment of die face pelletising, as it can shorten the process chain and leads to superior extrudate properties. The die faced pellets or granules are further filled into capsules or processed into tablets via conventional compaction devices and/or injection moulding. (Figure 1).

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Die Face Pelletising

The extruder produces homogeneous material, i.e., extrudates, which is shaped into the intermediate/product during downstream processing. A good overview of different pelletising processes is given by [5]. In the case of die face pelletising the molten material emerges from the extruder die plate as small strands, which are immediately cut into small particles, i.e., pellets, by a rotating knife. The outstanding advantage of die face pelletising is the production of spherical pellets with narrow particle size distributions. The spherical shape is due to the fact that the cutting takes place above the softening point of the material, where viscous forces allow the particles to contract and get spherical.

Sphero®-THA

The Sphero®-THA (Figure 2) is a novel die face pelletising system, which was developed by the project partner Automatik Plastics Machinery in close cooperation with the RCPE. It is designed to fulfil the GMP requirements and offers better processibility of sticky materials compared to conventional die face pelletisers.

http://www.youtube.com/watch?v=K3snC3sf8WE

A sectional view of our die face pelletizer is illustrated in Figure 3. The cutting chamber is penetrated by cooling air, which on the one hand cools the pellets and on the other hand conveys them into a product container or to a subsequent product handling step. The two main advantages of our system in comparison to conventional systems are the design of the knife and the increased cooling capacity. The knives are pressed on die plate and thus, smearing and film formation on the plate are prevented. The cooling capacity is increased due to adiabatic expansion of the cooling air at the entrance into the cutting chamber. The combined effects of knife design and cooling capacity enable cuttability of certain sticky materials. Figure 4 gives a few examples of materials that were processed via the Sphero®-THA, including (1) 80% calcium stearate 20% paracetamol [3], (2) ethylene vinyl actetate [6], (3) Kollidon VA64 and (4) 80% Eudragit EPO and 20% Talcum. The latter two materials show high stickiness and tend to agglomerate at the outlet, which makes die face pelletising complicating. However, due to the high cooling capacity of the Sphero-THA these obstacles can be overcome.

Pellet Properties

In addition to material properties the flowability is a strong function of the pellet shape, i.e., pellet sphericity. When using a die face pelletising system, the mean pellet size is determined by the number of knives and their rotational speed, and by the material throughput and die plate configuration. Figure 5.1 shows the size distributions (generated from the circle equivalent pellet diameter with QICPIC, Sympatec) of pellets that were either processed by a strand cutter or by the Sphero®-THA. Clearly, the Sphero®-THA produces pellets with a narrow size distribution, whereas after strand cutting the distribution is broadened. However, the major advantage of the Sphero®-THA is that the sphericity can be improved significantly. The deformation to a sphere after the cutting process depends on the rheology and surface tension. A good process parameter set can lead to almost spherical pellets. An example of pellets produced via the Sphero®-THA are close to one (Figure 5.2), indicating an almost spherical shape resulting in excellent flowability. A visual comparison the investigated pellets is shown in Figure 6.

Figure 7 shows the surface morphology of pellets with a diameter of approximately 1 mm produced by the Sphero®-THA. Despite some cracks that were probably generated due to comparatively rapid cooling and/or the material properties the surface is rather smooth and regular.

Outlook

A mechanistic understanding of the pellet formation process is the focus of our work and is based on detailed material and process characterisation, such as viscosity and melt behaviour, miscibility, thermal behaviour and power input, just to mention some examples. Additionally, mechanistic models will be established and used in the future to allow a prediction of processibility by die face pelletising.

PSSRC Facilities

The area “Pharmaceutical Engineering and Particle Technology” at the institute of process and particle engineering has developed from a group of researchers around Prof. Johannes Khinast in autumn 2005. Initially focused on catalysis and direct numerical simulations of bubbly flows, Prof. Khinast’s group has formed three sub-groups dedicated to research in the fields of applied chemistry and continuous processing, manufacturing processes for the pharmaceutical industry, and simulation science. In a highly interdisciplinary environment, our area is eager to gain a more fundamental understanding of

transport process in (bio-)reactors,

the production of heterogeneous catalysts and (nano-)particles,

(chromatographic) separation processes,

hot melt extrusion

multiphase and granular flows, as well as

transport processes in complex fluids.

A main focus with respect to teaching is the training of students in the area of pharmaceutical engineering, transport phenomena and particle technology. Our research complements that of our sister organisation “Research Center Pharmaceutical Engineering GmbH”, and is tightly connected to leading national and international research institutions. This makes our area an attractive partner for industry, and brings us into the position to apply and win Austrian and European wide research grants.